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The Journal of Immunology, 1998, 160: 4662-4665.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: The B Cell Surface Protein CD72 Recruits the Tyrosine Phosphatase SHP-1 upon Tyrosine Phosphorylation1

Takahiro Adachi*, Heinrich Flaswinkel2,{dagger}, Hidetaka Yakura{ddagger}, Michael Reth{dagger} and Takeshi Tsubata3,*

* Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan; {dagger} Department of Molecular Immunology, Biology III, Freiburg University, Freiburg, Germany; and {ddagger} Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Activation signals of lymphocytes are negatively regulated by the membrane molecules carrying the immunoreceptor tyrosine-based inhibition motif (ITIM). Upon tyrosine phosphorylation, ITIMs recruit SH2-containing phosphatases such as SHP-1, resulting in down-modulation of cell activation. We showed that the cytoplasmic domain of the CD72 molecule carries an ITIM and is associated in vitro with SHP-1 upon tyrosine phosphorylation. Moreover, cross-linking of B cell Ag receptor (BCR) enhances both tyrosine phosphorylation of CD72 and association of CD72 with SHP-1 in B cell line WEHI-231. These results indicate that CD72 recruits SHP-1 upon tyrosine phosphorylation induced by BCR signaling, suggesting that CD72 is a negative regulator of BCR signaling.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Most lymphocyte activation signals such as those delivered via the Ag receptor involve phosphorylation of signaling molecules by specific kinases. The activation signals are negatively regulated by various membrane molecules such as the killer cell inhibitory receptor (KIR),4 CD94/NKG2, and Ly-49 in NK cells, the low-affinity Fc receptor for IgG (Fc{gamma}R)IIB and CD22 in B cells, ILT2 (LIR-1) in B cells and monocytes, ILT3 in myeloid cells, gp49 in NK and mast cells, and LAIR-1 expressed in the majority of leukocytes (1, 2, 3). Those molecules contain the conserved immunoreceptor tyrosine-based inhibition motif (ITIM) in the cytoplasmic domain (4, 5, 6). When the tyrosine residue in the ITIM is phosphorylated, the ITIM recruits Src homology 2 (SH2)-containing phosphatases, such as protein tyrosine phosphatase SHP-1, and SH2-containing inositol 5-phosphatase (SHIP) (7, 8, 9, 10, 11, 12). Those phosphatases have been shown to down-modulate the cell activation presumably by dephosphorylating the signaling molecules. NK cells express ITIM-containing molecules of two distinct families: KIR, gp49, and LAIR-1 are members of the Ig superfamily, while Ly-49 and CD94/NKG2 are type II membrane molecules carrying a C-type lectin domain (2, 3). Although B cells express members of the Ig superfamily carrying ITIMs such as Fc{gamma}RIIB, CD22, and ILT-2 (3), an inhibitory receptor carrying C-type lectin domain has not yet been identified.

CD72 (Lyb-2) is a 45-kDa type II membrane protein carrying a C-type lectin domain and is expressed on B lineage cells as a homodimer (13, 14, 15, 16). Treatment with anti-CD72 has been shown to augment the activation of B cells induced by B cell Ag receptor (BCR) signaling (17, 18, 19). Recently, we demonstrated that an anti-CD72 Ab blocks BCR-mediated cell death of mature B cells (20). These findings suggest that CD72 ligation modulates BCR signaling. Here, we demonstrate that the cytoplasmic domain of CD72 carries an ITIM and recruits SHP-1 upon tyrosine phosphorylation. Moreover, BCR signaling enhances phosphorylation of CD72 and its recruitment of SHP-1. Since it has been suggested that SHP-1 negatively regulates activation signals, including the one via BCR (1, 2, 3, 7, 9, 21, 22), BCR signaling may be negatively regulated by CD72.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cells

The mouse B lymphoma cell line WEHI-231 was cultured as described previously (23). In some experiments, WEHI-231 was cultured with 10 µg/ml of F(ab')2 fragments of goat anti-mouse IgM Ab (ICN Pharmaceuticals, Aurora, OH) or anti-mouse CD72a mAb 9-6.1 (18). The CD72a cDNA was obtained from total RNA prepared from a DBA/2 spleen by RT-PCR using a set of primers (5'-CCGAATTCATGGCTGACGCTATCACG-3' and 5'-AAGCGGCCGCTATATCCGGTTCAGTTCAG-3' (15). The CD72a cDNA was subcloned into an expression vector, pMik-neo (a gift of Dr. K. Maruyama, Tokyo Medical and Dental University) (pMikCD72). Transfection of WEHI-231 was done as described previously (23).

In vitro phosphorylation and association of glutathione S-transferase (GST) fusion proteins

The cDNA encoding the cytoplasmic domain of CD72 was obtained by PCR with a set of primers (5'-CCGAATTCATGGCTGACGCTATCACG-3' and 5'-CCGTCGACGTTTTGCAAGCAGACCGT-3') and subcloned into the EcoRI-SalI sites of the pGEX vector (Pharmacia, Uppsala, Sweden), resulting in pGEX-CD72 coding for a GST-CD72 fusion protein. For constructing the pGEX-Y7, pGEX-Y32, and pGEX-Y39 expression plasmids encoding GST fusion proteins containing peptides surrounding Y7 (AITYADLRFV), Y32 (CEAYEDGELT), and Y39 (ELTYENVQVS), respectively, we synthesized oligonucleotide pairs encoding the peptides (5'-AATTCGCTATCACGTATGCAGACCTGCGCTTTGTGG-3' and 5'-TCGACCACAAAGCGCAGGTCTGCATACGTGATAGCG-3' for Y7; 5 '-AATTCTGTGAGGCCTATGAAGATGGGGAACTCACCG-3' and 5'-TCGACGGTGAGTTCCCCATCTTCATAGGCCTCACAG-3' for Y32; and 5'-AATTCGAACTCACCTACGAGAACGTGCAAGTGTCTG-3' and 5'-TCGACAGACACTTGCACGTTCTCGTAGGTGACTTCG-3' for Y39). Oligonucleotide pairs were annealed and inserted into the EcoRI-XhoI sites of the pGEX vector. The GST fusion protein (10 µg) were phosphorylated by incubation with Sf9 cell lysates containing Lyn or Syk in in vitro kinase buffer (24). The cDNA encoding murine SHP-1 (25) was generated from total RNA of WEHI-231 by RT-PCR using a set of primers (5'-CCGAATTCGAACCCCAGGATGGTGAGG-3' and 5'-AAGATCGACTCACTTCCTCTTGAGAGA-3') and subcloned into the EcoRI-SalI sites of the pBluescript vector. The 35S-labeled SHP-1 proteins were synthesized in the presence of L-[35S]methionine using TNT-coupled in vitro translation kit (Promega, Madison, WI) and incubated with phosphorylated or unphosphorylated GST fusion proteins together with glutathione-coupled beads (Pharmacia) for 30 min at 4°C. Proteins precipitated with glutathione-coupled beads were subjected to SDS-PAGE, and the 35S-labeled proteins were visualized by autoradiography.

Immunoprecipitation and Western blotting

Cell lysates were incubated with 5 µg of anti-CD72 mAb 9-6.1 or anti-CD22 mAb Lyb-8.2 (PharMingen, San Diego, CA) and 30 µl of protein G-Sepharose (Pharmacia), and immunoprecipitation was done as described previously (26). Immune complexes were subjected to SDS-PAGE. Western blotting was done using peroxidase-conjugated anti-phosphotyrosine mAb 4G10, rabbit anti-SHP-1 (Upstate Biotechnology, Lake Placid, NY), and anti-SHIP (a kind gift of Dr. J. V. Ravetch, Rockefeller University, New York, NY) or rabbit anti-CD72 Abs generated against GST-CD72.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
The surrounding sequences of Y7 (ITYADL) in the cytoplasmic domain of CD72 completely match the consensus sequence of ITIM (V/IxYxxL/V). Since KIR ITIM has been shown to be phosphorylated by the Src family tyrosine kinase Lck (27), we examined whether the cytoplasmic domain of CD72 is phosphorylated in vitro by the Src family tyrosine kinase Lyn and the cytoplasmic tyrosine kinase Syk expressed in B cells. GST fusion proteins containing the cytoplasmic domain of CD72 (GST-CD72) were incubated with Sf9 cell lysates expressing either Lyn or Syk, and the phosphorylation of GST-CD72 was examined by Western blotting using anti-phosphotyrosine Ab. Whereas GST alone was not phosphorylated by Lyn or Syk (Fig. 1Go, lanes 3 and 5), GST-CD72 was phosphorylated by both tyrosine kinases (lanes 4 and 6), indicating that CD72 is a potential substrate of Lyn and Syk expressed in B cells.



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  		FIGURE 1. Phosphorylation of CD72 fusion proteins by Lyn or Syk. Ten micrograms of GST (lanes 1, 3, and 5) or GST-CD72 fusion protein (lanes 2, 4, and 6) was incubated with the lysates of Sf9 cells infected with a baculovirus carrying lyn (lanes 3 and 4) or syk (lanes 5 and 6) in the in vitro kinase buffer (30) for 15 min at 37°C. Proteins were subjected to SDS-PAGE, followed by Western blotting. As a negative control, the same amount of untreated GST and GST-CD72 was analyzed in parallel (lane 1 and 2). Upper panel, The membrane was probed with anti-phosphotyrosine mAb 4G10. Lower panel, The SDS-polyacrylamide gel was stained with Coomassie brilliant blue.

 
Tyrosine-phosphorylated ITIMs have been shown to recruit SH2-containing phosphatases such as SHP-1 (1, 2, 7, 8, 9, 11, 12). To ask whether SHP-1 is able to associate with the cytoplasmic domain of CD72 upon tyrosine phosphorylation, we synthesized 35S-labeled SHP-1 by in vitro translation and incubated the phosphatase with GST-CD72 either unphosphorylated or phosphorylated by Lyn. Although equivalent amounts of phosphorylated or unphosphorylated GST-CD72 were incubated with SHP-1 (Fig. 2GoA), SHP-1 was coprecipitated with tyrosine-phosphorylated GST-CD72 but not by unphosphorylated GST-CD72 (Fig. 2GoB). This result indicates that the cytoplasmic tail of CD72 can bind to SHP-1 upon tyrosine phosphorylation as is the case for other membrane molecules carrying ITIMs (1, 2, 7, 8, 9, 11, 12).



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  		FIGURE 2. Tyrosine-phosphorylated CD72 associates with SHP-1 in vitro. GST-CD72 was phosphorylated as described in the legend to Figure 1Go except that the reaction was prolonged to 30 min. A, GST-CD72 fusion proteins treated with Lyn or untreated were subjected to SDS-PAGE, followed by Western blotting using rabbit anti-mouse CD72 Abs. B, 35S-labeled SHP-1 proteins were incubated with either phosphorylated (lane 2) or unphosphorylated GST-CD72 (lane 1) together with glutathione-coupled beads for 30 min at 4°C. The beads were washed with PBS three times and incubated with SDS-PAGE sample buffer. Proteins were separated by SDS-PAGE. 35S-labeled proteins were visualized by autoradiography. C, GST-Y7 (lane 1), GST-Y32 (lane 2), GST-Y39 (lane 3), and GST-CD72 (lane 4) fusion proteins were incubated with Lyn and subsequently with 35S-labeled SHP-1. Proteins were precipitated with glutathione-coupled beads and subjected to SDS-PAGE. 35S-labeled proteins were visualized by autoradiography. D, GST-Y7 (lane 1), GST-Y32 (lane 2), and GST-Y39 (lane 3) fusion proteins were incubated with Lyn and subjected to SDS-PAGE, followed by Western blotting using 4G10 mAb.

 
Among three tyrosine residues in the cytoplasmic domain of CD72 (amino acid residues number 7, 32, and 39), surrounding sequences of Y7 fit to the consensus sequence of ITIM. Moreover, the sequences surrounding Y39 (LTYENV) are similar to the consensus sequence of ITIM. To determine the tyrosines responsible for association with SHP-1, we prepared GST fusion proteins containing peptides surrounding either Y7, Y32, or Y39. When the fusion proteins were incubated with Lyn, both Y7 and Y39, but not Y32, were phosphorylated (Fig. 2GoD). However, SHP-1 was coprecipitated with the GST fusion protein containing Y7, but not Y32 or Y39 (lanes 1–3, Fig. 2GoC). SHP-1 may thus associate with the ITIM surrounding Y7 but not the ITIM-like sequence containing Y39 upon phosphorylation.

To test whether the cytoplasmic domain of CD72 recruits SH2-containing phosphatases upon phosphorylation in vivo, we transfected the CD72a cDNA into the B lymphoma line WEHI-231 expressing CD72b but not CD72a. Cell lysates from positive transfectants (WEHI-CD72) were precipitated with anti-CD72 mAb (9-6.1) recognizing CD72a but not CD72b (28). Western blotting of the immunoprecipitates revealed that CD72 is weakly phosphorylated in untreated WEHI-CD72 (4G10 blot in Fig. 3Go). However, tyrosine phosphorylation of CD72 was not increased by treatment with anti-CD72 mAb (data not shown). Because 1) CD72 is comodulated with BCR (29), and 2) CD72 is phosphorylated in vitro by BCR-associated kinases Lyn and Syk (Fig. 1Go), we hypothesized that BCR cross-linking enhances phosphorylation of CD72. Indeed, treatment of WEHI-CD72 cells with F(ab')2 fragments of anti-IgM Abs enhanced tyrosine phosphorylation of CD72 together with other substrates coprecipitated with CD72 (4G10 blot in Fig. 3Go). We thus assessed whether SH2-containing phosphatases are coprecipitated with CD72 in BCR-cross-linked WEHI-CD72 cells. Because CD22 has been shown to be phosphorylated and recruit SHP-1 upon BCR cross-linking, we precipitated the lysates with anti-CD22 Ab in parallel as a positive control. In cell lysates prepared from untreated WEHI-CD72 cells, a small amount of SHP-1 was coprecipitated with CD72, whereas anti-CD22 failed to precipitate SHP-1 (anti-SHP-1 blot). When we treated WEHI-CD72 with anti-Ig, a markedly increased amount of SHP-1 was coprecipitated with CD72 or CD22 from the cell lysates, although equal amounts of cell lysates were tested. Indeed, almost the same amount of CD72 was precipitated from the lysates of anti-Ig-treated WEHI-CD72 as from the lysates of untreated WEHI-CD72 (anti-CD72 blot). Upon BCR cross-linking, CD72 appears to be phosphorylated less efficiently than CD22 (4G10 blot), presumably due to the fact that CD22 carries six tyrosines in the cytoplasmic tail whereas CD72 contains only three tyrosines. However, the amount of SHP-1 coprecipitated with CD72 in untreated and BCR-cross-linked WEHI-CD72 correlates with the extent of phosphorylation of CD72 (4G10 blot). It is therefore most likely that SHP-1 is recruited to CD72 upon phosphorylation in vivo as is the case for CD22. In contrast, we failed to detect SHIP in the anti-CD72 precipitates from WEHI-CD72 either untreated or treated with F(ab')2 fragments of anti-IgM, although a considerable amount of SHIP is expressed in WEHI-231 (data not shown). Thus, it is probable that CD72 does not recruit SHIP regardless of the phosphorylation of CD72. Taken together, tyrosine-phosphorylated CD72 may recruit SHP-1 but not SHIP.



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  		FIGURE 3. BCR signaling enhances tyrosine phosphorylation of CD72 and its association with SHP-1. WEHI-CD72 cells were incubated with or without 10 µg/ml of F(ab')2 fragments of anti-IgM Abs ({alpha}µ) for 3 min in RPMI 1640 medium, washed with PBS, and lysed in Triton X-100 lysis buffer. The lysates were incubated with 5 µg of either anti-CD72 mAb or anti-CD22 mAb together with 30 µl of protein G-Sepharose. Immune complexes were collected by centrifugation, washed three times with PBS, separated by SDS-PAGE, and subjected to Western blotting with indicated Abs. The bands representing CD72, determined by probing the membrane with rabbit anti-mouse CD72, are indicated. Note that two bands represent CD72, presumably due to differences in the m.w. between CD72a and CD72b (28). CD72b, which forms a dimer with CD72a, may also be precipitated with anti-CD72a Ab.

 
We demonstrated that CD72 recruits SHP-1 upon tyrosine phosphorylation both in vitro and in vivo. The ITIM sequence containing Y7 is responsible for association with SHP-1, in agreement with the previous findings that phosphorylated ITIMs in other membrane molecules associate with SH2-containing phosphatases such as SHP-1 (1, 2, 3, 7, 8, 11, 12). We also demonstrated that BCR signaling enhances phosphorylation of CD72 and its association with SHP-1 in WEHI-231 cells. Because 1) CD72 is comodulated with BCR (29) and 2) BCR-associated kinases Lyn and Syk are able to phosphorylate CD72 (Fig. 1Go), BCR-associated kinases activated by BCR cross-linking may phosphorylate CD72. Tyrosine-phosphorylated CD72 may subsequently recruit SHP-1, resulting in down-modulation of cell activation induced by BCR signaling. CD72 may, therefore, negatively regulate the cell activation induced by BCR ligation. The negative regulation of CD72 on BCR signaling may be enhanced or suppressed by treatment with anti-CD72 Ab. Indeed, anti-CD72 Ab have been shown to modulate the BCR signaling, resulting in augmentation of activation and abrogation of cell death in BCR-cross-linked B cells (17, 18, 19, 20). CD22, an ITIM-containing member of the Ig superfamily, is also associated with BCR and recruits SHP-1 upon BCR cross-linking, resulting in down-modulation of B cell activation induced by BCR signaling (30). Moreover, treatment with anti-CD22 Ab enhances B cell activation by BCR signaling by perturbing the negative regulation by CD22. CD72 may thus play a similar role to CD22 in the regulation of B cell function. Since CD72 carries a C-type lectin domain, activation signals in B cells may be negatively regulated by members of both the Ig superfamily and the C-type lectin family, as is the case for NK cells (2, 3).


   Acknowledgments
 
We are grateful to Drs. J. V. Ravetch (Rockefeller University) and K. Maruyama (Tokyo Medical and Dental University) for reagents, Dr. E. O. Long (National Institute of Allergy and Infectious Diseases) for helpful discussion, and Ms. Y. Shimokawa for technical assistance.


   Footnotes
 
1 This work was supported in part by grants from the Ministry of Education, Science, Sports, and Culture of Japan, the Science and Technology Agency of Japan, and the Uehara Memorial Foundation. Back

2 Present address: Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, D-81675 Munich, Germany. Back

3 Address correspondence and reprint requests to Dr. Takeshi Tsubata, Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan. E-mail address: Back

4 Abbreviations used in this paper: KIR, killer cell inhibitory receptor; BCR, B cell Ag receptor; ITIM, immunoreceptor tyrosine-based inhibition motif; GST, glutathione S-transferase; SH2, Src homology 2; SHIP, SH2-containing inositol 5-phosphatase. Back

Received for publication December 18, 1997. Accepted for publication March 17, 1998.


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